Temocillin use as a carbapenem-sparing option in a UK teaching hospital for treating serious Gram-negative bacterial infections

We read the article about temocillin for the treatment of invasive Enterobacterales infections with interest. 1 Temocillin is a narrow-spectrum penicillin with activity against ESBL-producing Enterobacterales (ESBL-PE). It could be used in place of carbapenems for some infections due to these infections (i.e. bacteraemia, pneumonia, urinary tract infection but not meningitis). 2 This option is becoming increasingly important in the era of emer-ging carbapenem resistance. Temocillin has also been shown to have less of an impact on the intestinal microbiota than cepha-losporins 3 or piperacillin/tazobactam. 4 We sought to determine the appropriateness, effectiveness and tolerability of temocillin prescribing in Cambridge University

We read the article about temocillin for the treatment of invasive Enterobacterales infections with interest. 1 Temocillin is a narrowspectrum penicillin with activity against ESBL-producing Enterobacterales (ESBL-PE). It could be used in place of carbapenems for some infections due to these infections (i.e. bacteraemia, pneumonia, urinary tract infection but not meningitis). 2 This option is becoming increasingly important in the era of emerging carbapenem resistance. Temocillin has also been shown to have less of an impact on the intestinal microbiota than cephalosporins 3 or piperacillin/tazobactam. 4 We sought to determine the appropriateness, effectiveness and tolerability of temocillin prescribing in Cambridge University Hospitals (CUH) NHS Foundation Trust. This was considered a service evaluation and ethical approval was not required.
We performed a single-centre retrospective data review of all adult inpatients who received temocillin between 1 October 2016 and 31 July 2017 at CUH. Temocillin was approved for use in CUH when a urine or blood culture isolate was confirmed to be an ESBL-PE and susceptible to temocillin (by BSAC methodology) and resistant to oral agents, in order to preserve carbapenems and piperacillin/tazobactam. Its use was therefore restricted to be only recommended by a microbiology consultant. As part of the formulary submission we were required to analyse its use to confirm it was used appropriately. It was used as monotherapy unless the microbiologist was concerned about polymicrobial infection.
Epidemiological data, duration of therapy and duration of carbapenem-sparing were recorded and analysed. Temocillin was dosed at 4 g/day (2 g IV q12h), except in cases of reduced renal function where dosing followed local guidance.
A total of 24 patients (14 male; 58%) were included. Two patients required two courses of therapy (total 26 courses) due to recurrence (one due to inadequate source control). The age of the patients ranged from 23-96 years (mean 69 years). Sixteen patients were cared by medicine/medicine for elderly, four by urology and two each by transplant and neurosurgery (Table 1).
Twenty-one episodes (81%) were bacteraemic; 19 of these were due to an ESBL-PE, whilst one had an AmpC-producing Escherichia coli and one had an E. coli with no ESBL or AmpC identified; three grew ESBL-PE in urine and two were commenced on temocillin as they had previously had ESBL-PE identified from urine/blood cultures.
Duration of therapy varied between 1 and 15 days (mean 6 days). Reasons for stopping temocillin included completion of course (13; 50%), 7 (27%) episodes of switching to ertapenem to facilitate outpatient parenteral antimicrobial therapy, one patient died and 5 (19%) episodes had other explanations. None of the discontinuations were due to intolerance/toxicity and there were no reported side effects. Renal function at the time of commencing temocillin varied greatly during the study, with glomerular filtration rate ranging from 5 to 218 mL/min (median 53 mL/min). There was, therefore, a wide range of dosing given. Overall, 19 (73%) had the correct dose, with 6 being underdosed and one being overdosed.
Two patients (8%) had recurrence of disease and one patient died. Patients had received 0-37 g (median 4 g) of meropenem prior to switching. Twenty-five (96%) of the episodes were improving on their previous regimen prior to switching to temocillin; they showed improvement 1 week after switch and 24 (92%) of these episodes showed improvement 1 month after switch. One patient was deteriorating prior to switching to temocillin and continued to deteriorate. Source control and switching back to meropenem occurred in this patient. One hundred and forty-eight days of total carbapenem-sparing was achieved.
We provide data on the use of temocillin as a carbapenemsparing agent in the management of serious ESBL-PE infections including 21 bacteraemic patients. Safe and effective alternatives are required in order to preserve carbapenems for seriously ill patients and prevent the emergence of resistance. Temocillin was used in patients with significant comorbidities. However, most patients had a urinary source and most patients were improving prior to switching to temocillin. Data supporting the use of temocillin for treating bacteraemic patients is currently limited to one case-control study 5 and three case series 1-3 involving 138 patients in total (26, 42, 40 and 30, respectively).
We found that dosing was inadequate according to renal function in six of our patients. This requires improvement, as appropriate dosing was associated with improved outcome in another study. 2 Important limitations include the single-centre study design involving a small number of patients with non-comparative data. In addition, the majority of patients were clinically and biochemically improving before antibiotics were switched to temocillin while awaiting susceptibility results.
Nevertheless, we believe that these data add to the current literature supporting the use of temocillin as follow-on therapy for treating serious infections, including bacteraemias, with limited treatment options, as a way to spare carbapenems. Further work is required, in the form of a prospective study or randomised control study to formally assess this further, such as that proposed by the ASTARTÉ trial. 6

Funding
This study was carried out as part of our routine work.

Ethics
This work was done as a service evaluation and did not require ethics approval. CCMS, Charlson comorbidity score; CRP, C-reactive protein; DME, Department of Medicine for the Elderly; F, female; GFR, glomerular filtration rate; HAP, hospital-associated pneumonia; M, male; n, no; na, not applicable; y, yes.